7.beta.-Acetylthio-17.beta.-(2-carboxyethyl)-17.beta.-hydroxyandrost-4-en-3 -one lactone (spironolactone) is a diuretic marketed both alone and with another diuretic (hydrochlorothiazide). See the Physicians Desk Reference 1978, pages 1537 and 1535, respectively.
A number of methods for preparing spironolactone (VIII) are known, see for example, U.S. Pat. Nos. 3,013,012, 3,413,288, 3,682,894, 3,847,906, 3,883,512, 3,894,006, 3,897,417, 3,900,467, 3,966,714, and 4,057,543. Besides the numerous patents which disclose processes for producing spironolactone (VIII) many other patents disclosed intermediates and processes for producing intermediates which have been reported as useful in various synthetic pathways leading to spironolactone.
U.S. Pat. No. 4,057,542 in Example 3 discloses a process for transforming ethisterone (I) to its hydroxy glycol (II).
The acid glycol (III) is novel. U.S. Pat. No. 2,705,712 (Example 1A) and U.S. Pat. No. 4,057,542 (Claim 11) disclose the corresponding glycol methyl ester compounds. U.S. Pat. No. 3,506,652 in Examples 1, 3 and 5 disclose other 17.beta.-hydroxyandrostenedione type compounds with 3-carbon side chains in the 17.alpha.-position which upon the appropriate reaction can be cyclized to form a lactone. Two process are known for adding a third carbon atom to the steroidal propargyl alcohol. U.S. Pat. No. 4,057,542 in Example 4 discloses the transformation of a 17.alpha.-ethinyl-17.beta.-hydroxy steroid to the corresponding 17.alpha.-(2-carboxyethinyl)-17.beta.-hydroxy methyl ester. However, this process is much different than the process utilized in the present invention. The process in U.S. Pat. No. 4,057,542, Example 4 first blocks the 17.beta.-hydroxy group, forms the 21-carboxylate methyl ester, and then removes the 17.beta.-hydroxy blocking group. The process of the present invention does not necessitate the blocking of the 17.beta.-hydroxy group but permits carboxylation of the 17.alpha.-ethinyl group directly. J. A. Cella et al. in J. Am. Chem. Soc. 79, 4808 (1957) describe reacting a 17.alpha.-ethinyl-17.beta.-hydroxy steroid [the 3.beta.-hydroxy analog of the hydroxy glycol (II)] with ethyl magnesium bromide and carbon dioxide to give the 3.beta.-hydroxy analog of the acid glycol (III).
The lactone (IV) is known, see U.S. Pat. No. 2,705,712 (claim 5). U.S. Pat. No. 4,057,542 (Example 5) discloses transformation of a 17.alpha.-(2-carboxyethinyl)-17.beta.-hydroxy steroid to its corresponding lactone by reduction of the acetylenic group by hydrogenation, lactonization and acid hydrolysis of the ketal at the C-3 position. That process is similar to one step of the process of the present invention.
The ester (V) is novel. U.S. Pat. No. 3,107,241 (Example 2) discloses 3.beta.-acetoxy-17.alpha.-(2-carboxyethyl)-17.beta.-hydroxyandrost-4,6-die ne lactone. In the ester (V) the saturation is 3,5- not 4,6-. U.S. Pat. No. 3,194,803 discloses 3-alkoxy-17.alpha.-(2-carboxyethyl)-17.beta.-hydroxyandrost-3,5-diene lactones. The compounds of formula (V) of the present invention are esters, not ethers. U.S. Pat. Nos. 3,159,622 (Example 1), 3,452,008 (Example 1), 4,069,219, 3,194,803 (Example 1), 3,107,241 (Example 2) disclose various processes for transformation of 3-keto steroids to the corresponding 3.beta.-acetoxy steroid.
The halo lactone (VI) is known where R.sub.6 is bromine, see U.S. Pat. No. 2,946,787. U.S. Pat. No. 2,946,787 (Example 5) discloses a process for the transformation of the lactone (IV) to the 6-bromolactone (VI). The process of U.S. Pat. No. 2,946,787 transforms the lactone (IV) directly to the halo lactone (VI) while the process of the present invention protects the 3-keto group as the acylate and therefore obtains a higher yield of halo lactone (VI).
The .DELTA.4,6-lactone (VII) is known, see U.S. Pat. No. 2,900,383. Even though U.S. Pat. No. 2,900,383 discloses the .DELTA.4,6-lactone (VII) it does not disclose any process similar to the process used in the present invention for transformation of the halo lactone (VI) to the .DELTA.4,6-lactone (VII).
U.S. Pat. No. 3,013,012 (Example 3) discloses a process for the transformation of the .DELTA.4,6-lactone (VII) to spironolactone (VIII).
A number of patents disclosed processes for preparing spironolactone (VIII), intermediates, or processes for producing intermediates useful in the various synthetic pathways to spironolactone (VIII). Even though the hydroxyglycol (II), the lactone (IV), the 6-bromolactone (VI) and the .DELTA.4,6 lactone (VII) are known, no patent alone or in combination teaches the very short and efficient processes of the present invention.